As an important organ of the body, the eyes are responsible for perceiving the external world. The eyes complete about 90% of the information obtained by human sensory organs from the outside world. The structure of the eye is delicate, and even a slight injury may cause structural changes, resulting in decreased or complete loss of visual function, resulting in immeasurable losses. [1] The eye has unique anatomical and physiological properties that limit the delivery of drugs to target ocular tissues/sites. Most ophthalmic drugs are administered topically in the conjunctival sac, most commonly in the form of eye drops. Affected by various physiological barriers, the ocular bioavailability of eye drops is extremely low, generally less than 5%. [4] Today, recent advances in the fields of pharmacy, biotechnology, and materials science are facilitating the development of novel ophthalmic dosage forms that provide sustained drug delivery, reduce dosing frequency, and increase the ocular bioavailability of drugs. [2]
Compared with traditional ocular drug delivery systems, ophthalmic nanoparticles have certain advantages in many aspects, such as bioavailability and drug release behavior. With the deepening of the research, people found that the properties of nanoparticles can be further improved after coating them with some high molecular substances such as polysaccharides and other polymers. Therefore, in recent years, research on the surface modification of drug-loaded nanoparticles has become an important link in the formulation optimization of ophthalmic nanoparticles. [4]
The development of nanotechnology allows
the effective delivery of ocular drugs. Schematic representation of common
nanocarriers, including (A) liposomes; (B) nano micelle; (C) dendrimers; (D)
nanoemulsions (on the left, oil-in-water; on the right, water-in-oil ); (E) Nanoparticles.
[3]
The use of nanocarriers in ocular drug delivery has shown the following advantages: 1) it can combine multiple drugs, including biomacromolecular drugs; 2) reduce the degradation of unstable drugs and achieve the effect of sustained and controlled release; 3) increase the correlation The residence time of the drug on the ocular surface to avoid frequent injections; 4) Improve the interaction of the drug with the corneal and conjunctival epithelium, thereby improving the bioavailability of the drug.
The ophthalmic nano drug delivery system
can be further made into dosage forms for convenient administration, such as
eye drops, submicroemulsion (nanoemulsion)/microemulsion, nanosuspension
(liquid preparation); gel (semi-solid preparation); film, intraocular inserts
(solid preparations), etc. [4]
Medicilon’s ophthalmic drug preparationservices cover four types: eye drops, injections, gels, and eye ointments. It has completed safety research on the preparations of various eye drops and vitreous injection new drugs and assisted in clinical approval.
New Nanotechnology Ophthalmic Preparation-Nanoemulsion
Microemulsion/nanoemulsion can be used for local drug delivery in the eye. The emulsion is composed of the oil phase, water phase, emulsifier, and co-emulsion agent, which can prolong the contact time between the drug and the corneal epithelial cells and promote the absorption of the drug by the cornea, sclera or conjunctiva. At the same time, some auxiliary materials can also be added to improve the adhesion of the emulsion. [1]
Microemulsions can solubilize insoluble drugs, protect easily hydrolyzed drugs, and prolong the release time of water-soluble drugs. Ester-containing microemulsions can change the fluidity of biological membranes and have a strong ability to promote penetration. The particle size of the microemulsion is small and uniform, which is good for absorption and greatly improves the bioavailability; the preparation process is simple and can be sterilized by filtration; the viscosity is low. Compared with ordinary eye drops, microemulsion can significantly increase drug concentration, prolong drug ocular retention, increase corneal permeability, improve bioavailability, reduce administration times, and reduce adverse reactions. [4]
Shen Jinqiu et al. used the shear homogenization process to prepare flurbiprofen axetil nanoemulsion-in-situ gel by mixing flurbiprofen axetil nanoemulsion with ion-sensitive gel material (gellan gum). Strong gelling ability, uniform particle size distribution of emulsion droplets, significantly prolonged corneal residence time, significantly improved ocular bioavailability can significantly prolong the ocular surface residence time of drugs and effectively reduce the eye irritation of the original drug. [1]
Preparation method of ophthalmic nanoemulsion
Comparison of Low Energy Method and High Energy Method
According to the amount of energy used in the process, the preparation methods of nanoemulsions can be divided into low-energy methods and high-energy methods. Low-energy methods include self-emulsification, solvent evaporation, phase inversion temperature (PIT) methods, or solvent displacement methods, and high-energy methods include high-energy mixing (high-energy agitation), high-pressure homogenization (HPH), micro fluidization, membrane emulsification, sonication, or Jet homogenization.
Self-emulsification method
Nano-oil droplets are dispersed in an aqueous water solution and a hydrophilic surfactant. The process of formulating nanoemulsions using the self-emulsification method utilizes the chemical energy released during the dilution of the internal phase with a continuous phase, usually at a constant temperature, without any phase transition during emulsification. Formation of nanoemulsions using the self-emulsification method is a two-step process. First, a bicontinuous microemulsion is formed at the interface between the organic and aqueous phases, which is subsequently disordered, leading to the spontaneous generation of fine oil droplets. The size of nanoemulsion droplets formed in this way is influenced by several factors, including the type and amount of surfactant and co-surfactant, the ratio between the surfactant and dispersed phase, the presence of additives in the dispersed phase, and the composition and viscosity.
Emulsification and solvent evaporation method
Ophthalmic nanoemulsions can also be obtained by self-emulsification after evaporation of the water-miscible organic solvent in which the oily phase is dissolved. In this method, a solvent and oil mixture is dispersed in a surfactant-added aqueous phase at room temperature. After mixing, the organic solvent diffuses rapidly into the water, and the oil is dispersed in the form of nano-sized droplets. At the end of this period, the solvent was evaporated from the emulsion under reduced pressure.
Phase inversion composition method (PIC) and phase inversion temperature method (PIT)
Low-energy methods also include phase inversion methods, which involve the internal phase being dispersed in the continuous phase due to changes in formulation composition (phase inversion composition method, PIC) or temperature (PIT). The phase inversion point is defined as the point at which the surface tension (about ten μN/m) between the water and oil phases enables the spontaneous formation of nanoparticle size without energy input.
High Pressure Homogenization Process (HPH)
The general protocol for preparing o/w nanoemulsions using high-energy methods begins with the initial homogenization of a mixture of oil, surfactant, and water with a high-shear mixer to form an emulsion (pre-emulsion). In the second step, the resulting pre-milk is homogenized with a high-pressure homogenizer using hydraulic shearing, intense turbulence, and cavitation.
In a high-pressure homogenizer, two immiscible liquids are added under high pressure (500−5000 psi or 35−445 bar), and an emulsifier is added through a piston gap of about a few microns to obtain a dispersed phase with a uniform particle size of about 10 nm particle size nanoemulsion—usually, multiple passes through the homogenizer. The final droplet size depends on the number of homogenization cycles and the composition of the formulation. In the industrial production of nanoemulsions, the most important advantages of high-pressure homogenization are the high efficiency, scalability, and repeatability of the process.
Microfluidization process
Microfluidization is also a direct emulsification process as it does not require pre-emulsification. The dispersed phase is injected directly into the continuous phase through microchannels, which has advantages over high-pressure homogenization methods. From a mechanical point of view, a microfluidic device is a static mixer with no moving parts capable of producing small droplets of a dispersed phase with a narrow size distribution. Furthermore, micro fluidization can be used for laboratory and industrial-scale formulations. Dukovski et al. successfully prepared uncoated and chitosan-coated ibuprofen nanoemulsions using microfluidics. For uncoated nanoemulsions, the oil phase consisting of ibuprofen dissolved in Miglyol 812 lecithin solution was first premixed with the aqueous solution of Kolliphor EL using a magnetic stirrer and then homogenized using a high-shear stirrer at 6000 rpm—quality for 5 minutes. The pre-emulsion obtained was treated in a microfluidizer for five cycles at a pressure of 1000 bar. Chitosan solution was added to the aqueous phase in a microfluidic device, mixed, and processed (1000 bar, five cycles) to obtain chitosan-coated nanoemulsions.
Ultrasonic process
During phacoemulsification, the energy required to break up the inner phase droplets of the emulsion is provided by an ultrasonic probe that emits high-frequency sound waves of at least 20 kHz. The sonotrode contains a piezoelectric quartz crystal that expands and contracts in solution in response to an applied AC voltage. When the tip of an ultrasonic probe comes into contact with a liquid, it generates mechanical vibrations, leading to cavitation (i.e., the formation and collapse of voids in the liquid due to a local drop in pressure to or below the vapor pressure of the liquid). The expansion force generated by the sound waves during the expansion phase triggers the destruction of the liquid structure. Cavitation leads to the formation of microjets (acoustic jets), shear stress, shock waves and turbulence in the fluid medium. The emulsification process using ultrasound is a two-stage process. Initially, waves breaking up dispersed-phase particles are formed in the acoustic field, and then acoustic cavitation occurs.
The temporary localized thinning and pressure drop as the sound waves propagate through the liquid favors the formation of microbubbles and their subsequent compaction and dispersal into smaller droplets due to pressure fluctuations. The droplet formation of nanoemulsions is controlled by the interplay between droplet breakup and droplet coalescence. Ultrasonic equipment is mainly used to obtain emulsion droplets with a size of 0.2 μm in the laboratory.
Medicilon Ophthalmic PreparationDevelopment Platform
In response to the needs of the
ophthalmology market, Medicilon has established an ophthalmic preparation
development platform to help the development of the ophthalmology industry. The
Medicilon Preparation Department can undertake the development of dosage forms,
including ophthalmic liquid preparations and ophthalmic semi-solid
preparations. Medicilon has solutions, suspensions, emulsions, gels, ointments,
creams, and other technologies. platform. The completed project categories
include eye drops 1, 2, and 4, all of which have been successfully declared and
are currently undergoing clinical trials. At the same time, Medicilon can
undertake preclinical research in ophthalmology. The ophthalmology platform has
a special intraocular drug delivery technology and is equipped with an advanced
ophthalmic surgery microscope. Animal species such as dogs, miniature pigs, and
non-human primates achieve unique fine-grained dosing.
[1]. Chen Zhi, Feng Yang, Zhu Ronggang. Research progress of ophthalmic pharmaceutical preparations [J]. Food and Drugs, 2012,14(05):213-216.
[2]. Furqan A. Maulvi, et al. Recent advances in ophthalmic preparations: Ocular barriers, dosage forms and routes of administration. International Journal of Pharmaceutics, Volume 608, 25 October 2021, 121105
[3]. Ruth M. Galindo-Camacho, et al. Therapeutic Approaches for Age-Related Macular Degeneration. International Journal of Molecular Sciences 23(19):11769
[4]. Jin Yiguang et al. Application of nanotechnology in drug delivery.
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